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Research Original Investigation

Survival Outcomes With Adjuvant Chemotherapy in Resected Major Salivary Gland Carcinoma

SGCs demonstrated 5-year OS rates of 54.2%and 38.5% for RT and CRT, respectively. Part of the lack of benefit fromCRTmay be the generally low efficacy of chemotherapy in SGCs. 43 To improve the effectiveness of systemic agents, targeted thera- pies are under evaluation. Overexpression of hormone recep- tors, including the androgen receptor, epidermal growth fac- tor receptor, ERBB2 , and c -kit, are a fewexamples of potential targets to control local and systemic disease; trials evaluating targeted agents thus far have had negative findings. 44-48 More novel RT techniques and technologies may be another area to improve outcomes in SGCs. The relative radioresistance of sali- vary tumors has led to investigations of high linear energy transfer RT, including neutrons, protons, and carbon. Neu- tron therapy was one of the first to be studied in SGCs, with early promising local control results. 49 Unfortunately, neu- tron therapy led to significant late adverse events, including dysphagia, pain, necrosis, ageusia, and trismus, andwhen also accounting for its limited availability, has not routinely been adopted. 49 More recently, several studies evaluating proton therapy have found favorable local control rates, suggesting that particle therapy may be an option for these challenging tumors. 50,51 In addition, carbon therapy for malignant tu- mors of the salivary glandwas recently evaluated in the study of combined treatment of these tumors with intensity- modulatedRT and carbon ions (COSMIC). 52 COSMICwas a pro- spective phase 2 trial of dose-escalated 24-Gy (relative bio- logical effectiveness) carbon followed by 50-Gy photon intensity-modulated RT. Reported 3-year local control, pro- gression-free survival, and OS rates were 81.9%, 57.9%, and 78.4%, respectively; the most common adverse effects in- cluded xerostomia (49%), hearing impairment (25%), and ad- verse ocular effects (20%). Longer follow-up will be needed to better characterize potential late sequelae. Of note, 52% of patients in the study developed metastatic disease, empha- sizing again the importance of better systemic management in combination with RT. Combining future molecular-driven therapies with more sophisticated RT techniques may im- prove the relatively poor survival outcomes in malignant tu- mors of the salivarygland inaddition to reducingpotential toxic effects observed with conventional CRT and perhaps identi- fying unique high-risk patients who may benefit more from combined-modality treatment. The NCDB confers several benefits over other population databases, including a larger sample size, broader inclusion of ages, and the availabilityof RTandchemotherapydetails. How- ever, the NCDB is limited by its retrospective nature and the potential for miscoding. Further, even with our large sample size, some of the subgroup analyses performed still appeared underpowered. Next, inherent selection bias may exist for those receiving CRT with potential additional risk factors not accounted for in the variables available in the NCDB, such as presence of extracapsular extension, which is only coded in a limitednumber of cases. In an attempt to account for suchbias, we note that our results persist under MVA and PSM analysis. Other limitations include the lack of documentation on che- motherapy. Although receipt and timingof chemotherapywere known, the specific chemotherapy agent and dose and the number of cycles administered were unknown. In addition,

Table 3. Summary of Subgroup Population Multivariate Analyses Comparing Adjuvant RT vs CRT

Multivariate Analysis a HR (95% CI)

Subgroup Population

P Value

Age, y <65

1.39 (1.10-1.77) 1.02 (0.79-1.30)

.006

≥65

.90

Charlson-Deyo comorbidity score b 0

1.29 (1.04-1.59) 1.33 (0.81-2.18)

.02 .27

≥1

Primary tumor site Parotid gland

1.23 (1.02-1.48) 1.13 (0.69-1.84)

.03 .64

Submandibular gland

Histologic type Mucoepidermoid carcinoma Adenoid cystic carcinoma

1.47 (1.12-1.93) 2.55 (0.90-7.24) 1.20 (0.93-1.55) 1.83 (0.70-4.78) 1.29 (0.39-4.27)

.006

.08 .16 .22 .68

Adenocarcinoma

Salivary duct carcinoma Acinic cell carcinoma

Tumor grade 2

1.88 (1.04-3.39) 1.19 (0.99-1.42)

.04 .06

3

Tumor stage T1-T2

0.88 (0.61-1.28) 1.37 (1.13-1.66)

.50

T3-T4

.002

Nodal stage N0

1.25 (0.81-1.93) 1.17 (0.97-1.41)

.31 .09

N1-N3

Margin status Negative

1.25 (0.96-1.63) 1.30 (1.03-1.66)

.10 .03

Positive

No. of chemotherapy agents Single

1.16 (0.94-1.44) 1.34 (1.03-1.74)

.17

demonstrate a higher mortality with CRT in malignant tu- mors of the salivary gland. Given the likelihood that treatment- related toxic effectsmay contribute to these outcomes, proper patient selection is critical in cases inwhich the additionof che- motherapy is being considered. Anumber of publications have identified independent prognostic factors associatedwith in- creased rates of recurrence. 4,41,42 For patients with multiple risk factors who are healthy enough to tolerate chemo- therapy, CRTmay be indicated.We hope that the results of the RTOG 1008 study clarify whether the addition of chemo- therapy improves outcomes in major SGCs. Progress is needed to improve OS for high-risk SGCs. For localized stages III and IV tumors of the salivary gland, 5-year OS ranged from 30% to 50%. 29 Our study of high-risk major accounted for age, sex, race, insurance status, median annual income, residence, facility type, Charlson-Deyo comorbidity score, tumor site, histologic type, tumor grade, T stage, N stage, and margin status. An HR greater than 1 indicates worse overall survival for CRT. b Indicates number of comorbidities. Multiple .03 Abbreviations: CRT, chemoradiotherapy; HR, hazard ratio; RT, radiotherapy. a Radiotherapy alone served as the reference group. Subgroup analyses above

JAMA Otolaryngology–Head & Neck Surgery November 2016 Volume 142, Number 11 (Reprinted)

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